Study to Evaluate the Efficacy and Safety of Benralizumab in Adult Patients With Mild to Moderate Persistent Asthma

Asthma Clinical Trial

Official title:

A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Benralizumab in Adult Patients With Mild to Moderate Persistent Asthma.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02322775
• Other study ID #: D3250C00032
• Secondary ID: 2014-004427-40
• Status: Completed
• Phase: Phase 3
• First received: December 19, 2014
• Last updated: August 14, 2017
• Start date: February 2, 2015
• Est. completion date: October 7, 2015

Study information

• Verified date: August 2017
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this trial is to confirm the safety and clinical benefit of benralizumab administration in asthma patients with mild to moderate persistent asthma in order to gain an understanding of the benefit/risk of benralizumab across the spectrum of asthma disease.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 211
• Est. completion date: October 7, 2015
• Est. primary completion date: October 7, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

Written informed consent for study participation must be obtained prior to any study related procedures being performed and according to international guidelines and/or applicable European Union (EU) guidelines.

• Female and male aged 18 to 75 years, inclusively, at the time of Visit 1.

• Weight of =40 kg.

• Evidence of asthma as documented by post-bronchodilator (post-BD) reversibility in FEV1 of = 12% demonstrated at Visit 2.

• Documented use of 1 of the following types of asthma therapy at time of informed consent: Low- to medium-dose ICS (ie, 100 to 500 µg fluticasone dry powder formulation equivalents total daily dose) with or without other controller medications, eg, an LTRA and/or theophylline or Low-dose ICS/LABA fixed combination therapy (eg, the lowest regular maintenance dose approved in the local country will meet this criterion)

• Morning pre-bronchodilator (pre-BD) FEV1 of > 50% to = 90% predicted at Visit 2.

Exclusion Criteria:

• Clinically important pulmonary disease other than asthma (eg, active lung infection, COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts (eg, allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome).

• Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric, or major physical impairment that is not stable in the opinion of the Investigator and could:

• Affect the safety of the patient throughout the study

• nfluence the findings of the studies or their interpretations,- Impede the patient's ability to complete the entire duration of study.

• Known history of allergy or reaction to the investigational product formulation.

• History of anaphylaxis to any biologic therapy.- History of Guillain-Barré syndrome.

• A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to standard of care therapy.- Acute upper or lower respiratory infections requiring antibiotics or antiviral medication within 30 days prior to the date informed consent is obtained or during the screening/run-in period.

• Any clinically significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during screening period, which in the opinion of the Investigator, may put the patient at risk because of his/her participation in the study, or may influence the results of the study, or the patient's ability to complete entire duration of the study.

• Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Patients with a history of hepatitis B vaccination without history of hepatitis B are allowed to enroll.

• A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test.

• History of cancer:

• Patients who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the patient is in remission and curative therapy was completed at least 12 months prior to the date informed consent was obtained.

• Patients who have had other malignancies are eligible provided that the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent was obtained

Related Conditions & MeSH terms

• Asthma

Intervention

Biological:
• Benralizumab
Benralizumab administered subcutaneously every 4 weeks
• Placebo
Placebo administered subcutaneously every 4 weeks

Locations

Country	Name	City	State
Canada	Research Site	Ajax	Ontario
Canada	Research Site	Burlington	Ontario
Canada	Research Site	Hamilton	Ontario
Canada	Research Site	Ottawa	Ontario
Canada	Research Site	Quebec
Canada	Research Site	Quebec
Canada	Research Site	St Charles Borromee	Quebec
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Trois Rivieres	Quebec
Canada	Research Site	Vancouver	British Columbia
Germany	Research Site	Bamberg
Germany	Research Site	Berlin
Germany	Research Site	Frankfurt
Germany	Research Site	Frankfurt/Main
Germany	Research Site	Hannover
Germany	Research Site	Neu-Isenburg
Hungary	Research Site	Balassagyarmat
Hungary	Research Site	Komárom
Hungary	Research Site	Miskolc
Hungary	Research Site	Pécs
Hungary	Research Site	Pécs
Hungary	Research Site	Százhalombatta
Poland	Research Site	Katowice
Poland	Research Site	Mragowo
Poland	Research Site	Ostrów Wielkopolski
Poland	Research Site	Pabianice
Poland	Research Site	Poznan
Poland	Research Site	Poznan
Poland	Research Site	Tarnów
Poland	Research Site	Wroclaw
Poland	Research Site	Wroclaw
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Humenne
Slovakia	Research Site	Kosice
Slovakia	Research Site	Levice
Slovakia	Research Site	Poprad
Slovakia	Research Site	Presov
Slovakia	Research Site	Vrable
Slovakia	Research Site	Zilina
United States	Research Site	Blue Island	Illinois
United States	Research Site	Charlotte	North Carolina
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Clearwater	Florida
United States	Research Site	El Paso	Texas
United States	Research Site	Grove City	Ohio
United States	Research Site	Los Angeles	California
United States	Research Site	Medford	Oregon
United States	Research Site	Monroe	North Carolina
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	Orlando	Florida
United States	Research Site	Raleigh	North Carolina
United States	Research Site	Rolling Hills Estates	California
United States	Research Site	San Antonio	Texas
United States	Research Site	Skillman	New Jersey
United States	Research Site	Spartanburg	South Carolina
United States	Research Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Canada,  Germany,  Hungary,  Poland,  Slovakia, 

References & Publications (1)

Ferguson GT, FitzGerald JM, Bleecker ER, Laviolette M, Bernstein D, LaForce C, Mansfield L, Barker P, Wu Y, Jison M, Goldman M; BISE Study Investigators. Benralizumab for patients with mild to moderate, persistent asthma (BISE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2017 Jul;5(7):568-576. doi: 10.1016/S2213-2600(17)30190-X. Epub 2017 May 22. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) (L) at Week 12	The FEV1 (L) change from baseline are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect repeated measures (MMRM) analysis with baseline blood eosinophil count (=300 cells/µL or <300 cells/µL), protocol specified visit (Week 4, Week 8, Week 12), region (Europe or North America) and treatment*visit interaction as fixed effects and baseline pre-bronchodilator FEV1 (L) as a covariate.; Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline, Week 4, Week 8 and Week 12
Secondary	Change From Baseline in Morning Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12	The changes from baseline of weekly average of morning PEF (L/min) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model for repeated measures (MMRM) with baseline blood eosinophil count (=300 cells/µL or <300 cells/µL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline morning PEF (L/min) as a covariate.; Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Secondary	Change From Baseline in Evening Peak Expiratory Flow (PEF) (L/Min) at Home at Week 12	The changes from baseline of weekly average of evening PEF (L/min) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model for repeated measures (MMRM) with baseline blood eosinophil count (=300 cells/µL or <300 cells/µL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline evening PEF (L/min) as a covariate.; Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Secondary	Change From Baseline in Total Asthma Symptom Score at Week 12	Asthma symptoms were recorded by the patient each morning and evening in the asthma daily diary. Symptoms were recorded using a scale of 0-3, where 0 indicates no asthma symptoms. The daily asthma symptom total score was calculated by taking the sum of the daytime score recorded in the evening and the nighttime score recorded the following morning. The weekly total asthma score was averaged from the daily scores over a 7 day period, with score ranging from 0 to 6, where 0 indicates no asthma symptoms. The changes from baseline of weekly total asthma score are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (=300 cells/µL or <300 cells/µL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline total asthma score as a covariate.; Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Secondary	Change From Baseline in Total Asthma Rescue Medication Use (Puffs) at Week 12	The number of rescue medication inhalations and nebulizer treatments taken were recorded by the patient in the asthma daily diary twice daily. The number of inhalations (puffs) per day was calculated as [number of night inhaler puffs] + 2 x [number of night nebulizer times] + number of day inhaler puffs + 2 x [number of day nebulizer times]. The changes from baseline in weekly total asthma rescue medication use (puffs) are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (=300 cells/µL or <300 cells/µL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline total asthma rescue medication use (puffs) as a covariate.; Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Secondary	Change From Baseline in Proportion of Nights With Nocturnal Awakenings at Week 12	Nocturnal awakenings due to asthma symptoms and requiring rescue medication use was recorded by the patient in the asthma daily diary each morning. Proportion of nights with nocturnal awakenings was defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data for awakening due to asthma. The outcome variable for proportion of nights with nocturnal awakenings was the change from baseline at Week 12 in weekly proportion of nights with nocturnal awakenings. The changes are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect model repeated measures (MMRM) with baseline blood eosinophil count (=300 cells/µL or <300 cells/µL), protocol specified visit, region (Europe or North America) and treatment*visit interaction as fixed effects and baseline proportion of nights with nocturnal awakenings as a covariate.; Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 and Week 12
Secondary	Change From Baseline in Mean ACQ-6 Score at Week 12	The asthma control questionnaire, ACQ-6, consists of six questions; all assessed on a 7-point scale from 0 to 6, where 0 represents good control and 6 represents poor control. The overall score is the mean of the responses to each of the six questions. The changes from baseline of ACQ-6 score are compared between benralizumab 30 mg Q4W and placebo by using the mixed-effect repeated measures (MMRM) with baseline blood eosinophil count (=300 cells/µL or <300 cells/µL), protocol specified visit (Week 4, Week 8, Week 12), region (Europe or North America) and treatment*visit interaction as fixed effects and baseline ACQ-6 score as a covariate.; Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline, Week 4, Week 8 and Week 12
Secondary	Asthma Exacerbations	An asthma exacerbation was defined as a worsening of asthma that led to use of systemic corticosteroids for at least 3 days (a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids) or an emergency room or urgent care visit (defined as evaluation and treatment for <24 hours in an emergency department or urgent care center) due to asthma that required systemic corticosteroids (as per above) or an inpatient hospitalization (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for =24 hours) due to asthma. Number of patients experiencing an event included in the definition of asthma exacerbation was presented.	Up to Week 12
Secondary	Change From Baseline in AQLQ(S)+12 Total and Domain Scores at Week 12	The asthma quality of life questionnaire for 12 years and older, AQLQ(S)+12, consists of 32 questions; all assessed on a 7-point scale from 7 to 1, where 7 represents no impairment and 1 represents severe impairment. The 4 individual domain scores (symptoms, activity limitations, emotional function, and environmental stimuli) are the means of the responses to the questions in each of the domains. The overall score is calculated as the mean response to all questions. The changes from baseline of AQLQ(S)+12 score are compared between benralizumab 30 mg Q4W and placebo by using the analyse of covariance (ANCOVA) with baseline blood eosinophil count (=300 cells/µL or <300 cells/µL) and region (Europe or North America) as fixed effects and baseline AQLQ(S)+12 score as a covariate.; Changes at Week 12 were calculated based on patients with both baseline and Week 12.	Baseline and Week 12
Secondary	Serum Concentrations (ng/mL)	Blood samples (processed to serum) for pharmacokinetic assessments were collected from all patients at baseline prior to first benralizumab administration at Day 1, at the Week 12 visit or the IP discontinuation visit, and at the Week 20 follow-up visit. Serum concentrations of benralizumab were determined using a validated electrochemiluminescent (ECL) immunoassay.	Baseline, Week 12 and Week 20
Secondary	Peripheral Blood Eosinophil Levels	Peripheral blood eosinophil levels assessments were collected from all patients at baseline prior to first benralizumab administration at Day 1, at the Week 12 visit or the IP discontinuation visit, and at the Week 20 follow-up visit.; Changes at Week 12 (respectively at Week 20) were calculated based on patients with both baseline and Week 12 (respectively Week 20).	Baseline, Week 12 and Week 20

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